The goal of this research program is to study the function of a novel photoreceptor specific cadherin (prCAD) that we recently identified. In our preliminary studies we showed that prCAD, a novel member of the cadherin family of cell adhesion proteins, is expressed only in retinal photoreceptors. We used immunoelectron microscopy to localize the prCAD protein to the margins of nascent membrane disks at the base of the photoreceptor outer segments (OS). We produced prCAD (-/-) mice and showed that in these mice the OS are disorganized and fragmented and there is progressive death of photoreceptor cells. The unique localization of prCAD to the base of the OS and the disrupted morphology of the OS in the mutant mice indicate an essential role for prCAD in the biosynthesis or maintenance of the outer segment. The prCAD (-/-) phenotype in the mouse and the high degree of conservation in the prCAD sequences between mice and humans predicts that mutations in human prCAD are likely to cause retinal diseases. We aim to (1) develop methods for expression of recombinant prCAD in photoreceptors of zebrafish and Xenopus to test the effect of mutations on the structure and function of this protein, (2) identify disease-associated mutations in human prCAD and study their function, (3) identify prCAD interacting proteins and study their role in outer segment morphogenesis, and (4) detect genes and signaling pathways that are differentially regulated in the prCAD (-/-) mouse retina.